Last updated:
2/27/2024
Years published: 1986, 1987, 1990, 1994, 1996, 2004, 2007, 2011, 2014, 2016, 2020, 2024
NORD gratefully acknowledges Nicole Kucine, MD, MS, Director of the Bloom Syndrome Registry, Chris Cunniff, MD, Associate Director of the Bloom Syndrome Registry and Katherine Langer, BA, Research Coordinator for the Bloom Syndrome Registry, for assistance in the preparation of this report.
Bloom syndrome (BSyn) is a rare genetic disorder characterized by short stature; a sun-sensitive, red rash that occurs primarily over the nose and cheeks; mild immune deficiency with increased susceptibility to infections; insulin resistance that resembles type 2 diabetes; and most importantly, a markedly increased susceptibility to many types of cancer, especially leukemia, lymphoma and colorectal tumors. Diagnosis typically involves identification of the characteristic clinical features and/or molecular testing to identify changes (variants) in the BLM gene. BSyn is inherited in an autosomal recessive pattern, meaning that it occurs when a person inherits two disease-causing variants in the BLM gene. Because the most common BLM variant is present at a high frequency in the Eastern European Jewish (Ashkenazi) population, it is often included among the Jewish genetic diseases. The genetic abnormality in Bloom syndrome causes problems with DNA repair, resulting in a high number of chromosome breaks and rearrangements. The abnormal DNA repair is responsible for the increased risk for cancer.
The most consistent clinical feature of BSyn, seen throughout all stages of life, is poor growth that affects height, weight and head circumference. This growth deficiency begins before birth, and the affected fetus is typically smaller than normal for gestational age. Body proportions are normal. The average adult height of affected males and females is below normal and the average head circumference was below normal at all ages in a study of 136 Bsyn patients.
The facial appearance of people with BSyn is variable and may be undistinguishable from unaffected persons of similar age and size, but infants and adults with Bloom syndrome usually have a narrow appearing head and face. Sparse subcutaneous fat may cause the nose and/or ears to appear prominent. Despite their small head circumference, most affected individuals have normal intellectual ability. Feeding difficulties are commonly reported in newborns, infants and young children with BSyn. The child with BSyn characteristically feeds slowly, has a decreased appetite and eats a limited variety of foods. Some infants have had feeding tubes placed. Despite these interventions, weight gain continues to be modest and children are rarely in the normal range for growth, even though their growth hormone levels are normal. Gastroesophageal reflux is common and may contribute to feeding issues.
Skin lesions are another hallmark of BSyn. Although the skin at birth and in infancy appears normal, a red rash later appears on the nose and cheeks in a butterfly shape, and sometimes on the hands and forearms due to the dilation of small blood vessels called telangiectasia. The skin is highly sensitive to sunlight (photosensitive) and this rash often occurs for the first time following sun exposure in the first or second year of life. Areas of abnormal brown or gray skin coloration (cafe-au-lait spots) may occur on other parts of the body.
Males with Bloom syndrome are unable to produce normal amounts of sperm and are usually sterile. There has been one confirmed case of a male with BSyn fathering a child. Female infertility may also occur because menstruation ceases at an abnormally early age among females with Bloom syndrome. However, eleven females in the Bloom Syndrome Registry have become pregnant at least once, seven of whom have delivered a total of eleven healthy babies of normal size.
Many people with BSyn show signs of immune deficiency. As a result, they can experience recurrent infections, primarily ear infections and respiratory infections. Although infections appear to be more common in people with Bloom syndrome, these infections are not life threatening and usually respond to standard antibiotic treatment. People with Bloom syndrome can also have endocrine abnormalities, and about 17% of patients in the Bloom Syndrome Registry have developed diabetes. Hypothyroidism, a condition that occurs when the thyroid gland does not make enough thyroid hormone (which is important for metabolism, growth and other bodily functions) has been reported in people with Bloom syndrome as well.
By age 40, a little over 80% of people with Bloom syndrome develop at least one of a variety of cancers, especially leukemia or lymphoma. The types and locations of cancer are similar though not identical to those seen in the general population, but cancer occurs more frequently and at earlier ages in people with BSyn. Of the 294 persons in the Bloom Syndrome Registry, 155 individuals (53%) have developed a total of 251 cancers. Solid tumors account for 66.9% of all cancers, compared to 33.1% with leukemia/lymphoma. Among solid tumors, colorectal cancer is most common at 30 cases to date, followed by skin cancer (29 cases), then breast and oropharyngeal cancers (29 and 28 cases respectively). One-third of the people who have developed cancer develop multiple cancers.
People with Bloom syndrome appear to have 150-300 times the risk of developing cancerous growths as do people without this condition. Most people with Bloom syndrome are likely to develop cancer over their lifetime.
Bloom syndrome is caused by disease-causing variants in the BLM gene. The BLM gene is responsible for making a protein known as BLM. The BLM protein that is abnormal in people with Bloom syndrome is a RecQ helicase. Helicases help in DNA replication and repair by temporarily “unzipping” or “unwinding” the double helix of DNA so that it can be replicated. When this helicase is defective, as is the case in BSyn, a cell cannot detect and repair errors as effectively. This means that DNA damage during the course of a cell’s life is not found and repaired, so the cell cannot continue to function. The cell may die, or in some cases the damaged cells may continue to grow in an abnormal fashion and result in cancer.
Bloom syndrome is inherited in an autosomal recessive pattern. This means that affected persons have a disease-causing variant in both copies of the BLM gene, one inherited from each parent. Both parents have one copy of a BLM gene variant and one copy of a normal BLM gene. The risk for two carrier parents to both pass down the disease-causing variant and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
A specific variant , known as BLMAsh, is responsible for over 90% cases of Bloom syndrome among Ashkenazi Jews.
Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Bloom syndrome is of special interest to geneticists because patients with this condition have chromosomes that are highly unstable, so gene variants are frequently encountered. In addition, the recombination of chromosomes in Bloom syndrome patients occurs with much greater frequency and seemingly with much greater ease than normal. Most clinicians engaged in studies of Bloom syndrome consider the volatility of the chromosomes to be a major contributor to both short stature and a predisposition to cancer.
One of the types of chromosomal recombination that occurs in Bloom syndrome because of variants in the BLM gene is known as sister-chromatid exchange (SCE). This means that portions of the chromosomal-DNA are exchanged among paired (sister) chromosomes. Whereas persons without BSyn have an average SCE rate of <10 per cell division (metaphase), individuals with BSyn average 40-100 SCEs per metaphase. Previously, Bloom syndrome was the only known human genetic condition in which cells undergo high levels of SCE and therefore the presence of multiple SCE’s was a diagnostic indicator. However, SCE analysis alone is no longer sufficient to confirm a diagnosis of BSyn, because increased SCEs have since been observed in persons with genetic disorders that are caused by abnormalities of the RMI1, RMI2 or TOP3A genes. Nonetheless, SCE analysis may be useful for diagnosis of BSyn in circumstances where only one BLM variant is identified and molecular genetic testing finds no variants in RMI1, RMI2 or TOP3A.
Bloom syndrome is rare, with about 294 cases reported to the Bloom Syndrome Registry. Although it occurs in many ethnic groups, it is more prevalent in people of Ashkenazi Jewish heritage whose ancestors were from Poland or the Ukraine. Among Ashkenazi Jews living in the U.S, the carrier frequency is about one in 157. Among Ashkenazi Jews living in Israel, the carrier frequency is about one in 111. Bloom syndrome has been diagnosed in people all over the world, and about 75% of cases occur in people who are not of Jewish ancestry.
The treatment of Bloom syndrome is symptomatic and supportive. Health supervision recommendations that address diagnosis, treatment and surveillance for complications in persons with Bloom syndrome have been published [Cunniff et al. 2018].
To prevent skin cancer and the typical red rash that is common in BSyn, persons with Bloom syndrome should limit contact with direct sunlight by seeking shade, especially between 10 a.m. and 4 p.m. Health recommendations also suggest covering exposed skin with clothing, including a broad-brimmed hat and UV-blocking sunglasses and applying a broad-spectrum sunscreen with SPF of 30 twice daily, or every 2-3 hours if outdoors. Annual evaluation by a dermatologist is also advised.
Family members, friends and teachers are encouraged to relate to persons with BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Nonetheless, infants, toddlers, and preschool-age children with BSyn should have close developmental monitoring and referral for early intervention services. If developmental delays are present, physical, occupational and speech therapy can help. School performance should be assessed regularly and parents should be aware of educational support available.
Growth hormone therapy for children with BSyn has not consistently increased growth rate in most children, but some have had improved linear growth. Use of growth hormone has been approached cautiously in childrden with Bloom syndrome because of concerns about an increased risk to develop tumors as a result of this treatment. If growth hormone is prescribed, the growth response and serum IGF-1 and IGFBP-3 levels should be closely monitored, and unless there is an increase in growth velocity while under treatment, it should be discontinued.
Because of an increased incidence of hypothyroidism in people with BSyn, serum TSH with reflex to T4 should be measured annually beginning at 10 years. Additionally, recent health supervision guidelines suggest screening and family education on the signs and symptoms of hypothyroidism, including fatigue, constipation, cold sensitivity and weight gain.
Until additional information is available regarding treatment of problematic feeding behaviors and gastrointestinal symptoms, standard treatment for these concerns is recommended. This may include consultation with a gastroenterologist or feeding specialist, use of high calorie diets, use of reflux precautions and use of anti-reflux medications. While supplemental feeding may result in increased fat deposition, it does not necessarily result in improved linear growth. Because abnormalities have been identified in the lipid profile of persons with BSyn, patients should avoid a high fat and/or high cholesterol diet. A lipid profile to detect dyslipidemia is recommended annually beginning at 10 years; for those with dyslipidemia, dietary treatment according to standard protocols is recommended.
Type 2 diabetes mellitus is common in people with BSyn, so fasting blood glucose and hemoglobin A1C should be measured annually beginning at 10 years, and patients, their families, and their doctors should be alert for signs and symptoms such as increased thirst, increased urination and weight loss. Treatment of type 2 diabetes in BSyn is the same as for other people with type 2 diabetes.
For those with certain defects in of the immune system, weekly subcutaneous or monthly intravenous gamma globulin treatment may be beneficial. Cough assist devices, vibration vests and daily nasal lavage can be used to for mucociliary clearance for bronchiectasis. If an individual with BSyn experiences recurrent, severe or opportunistic infection, then immunodeficiency screening, including immunoglobulin level, antibody responses to vaccines and quantitative B and T lymphocyte measurements, are recommended.
Physicians must watch for indications of cancer, especially in adult patients. A timeline for when to begin the suggested screenings and how often they should be done has been published [Cunniff et al. 2018]. It should be recognized however, that these recommendations are based on limited data from the Bloom Syndrome Registry and on expert opinion. There are currently no clinical trials or case control studies that address outcomes in people with BSyn. Because of the unusually high risk for early development of cancer, much of the health supervision effort is directed to early detection and treatment.
For pediatric patients, recent health supervision guidelines suggest screening for Wilms tumor by performing an abdominal ultrasound every 3 months from the age of diagnosis until 8 years, in addition to screening for signs and symptoms such as hematuria and a painless abdominal mass. Surveillance for hematological cancers largely depends on awareness of signs and symptoms, including unintentional weight loss and fatigue, pallor, abnormal bleeding and petechiae when surveilling for leukemia and enlarged lymph nodes, unexplained fevers and drenching night sweats for lymphoma. Screening for colorectal cancer should begin at 10-12 years, with an colonoscopy every 1-2 years and fecal immunochemical testing (FIT) every 6 months. In affected females over the age of 18, a breast MRI to detect breast cancer is recommended annually. The most recent guidelines also recommend a whole-body MRI every 1-2 years beginning at age 12 or 13 to detect other solid tumors or lymphomas.
When treating cancer, the hypersensitivity of persons with BSyn to both DNA-damaging chemicals and ionizing radiation usually requires modification of standard cancer treatment regimens, such as a reduction of both dosage and duration. Individuals with BSyn have usually tolerated doses at or below 50% of the standard chemotherapy dosage, with no clear evidence that this has resulted in poorer outcomes. However, full weight-based dosing may be appropriate for some chemotherapeutic drugs such as steroids and tyrosine kinase inhibitors. Lack of information about the ideal dosages makes treatment particularly challenging, but the cancers are often unusually responsive to the treatment so the special effort is recommended. If stem cell transplantation is being considered, nonmyeloablative transplantation is likely to be tolerated more readily than other regimens. Additionally, the required ablative therapy prior to a bone marrow transplant may require modification of standard protocols because of the hypersensitivity of persons with BSyn to DNA-damaging agents.
Because infertility is a common issue, males with BSyn can undergo semen analysis after puberty to look for abnormalities in the quantity and motility of sperm (azoospermia, oligospermia or asthenospermia). After puberty, females with BSyn should be aware of signs of early menopause and may also consider oocyte (egg) freezing (cryopreservation). Additionally, assisted reproductive technology (ART) may be beneficial if natural conception is not possible, but there are currently no reports of ART in people with Bloom syndrome. Patients who wish to conceive should consider consulting with a fertility specialist.
Genetic counseling is recommended for people with Bloom syndrome and their families. Preimplantation and prenatal diagnosis are possible if the BLM gene variants have been identified in the parents.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
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REVIEW ARTICLES
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JOURNAL ARTICLES
Cunniff C, Djavid AR, Carrubba S, et al. Health supervision for people with Bloom Syndrome. Am J Med Genet Part A. 2018;176A:1872– 1881.
https://www.ncbi.nlm.nih.gov/pubmed/30055079
Martin CA, Sarlós K, Logan CV, et al. Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Hum Genet. 2018;103:221–231. https://www.ncbi.nlm.nih.gov/pubmed/30057030
Hudson DF, Amor DJ, Boys A, et al. Loss of RMI2 Increases Genome Instability and Causes a Bloom-Like Syndrome. 2016 Dec 15. In: Maizels N, editor. PLOS Genetics. 2016;12(12). https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006483
Fares F, Badarneh K, Abosaleh M, Harari-Shaham A, Diukman R, David M. Carrier frequency of autosomal-recessive disorders in the Ashkenazi Jewish population: should the rationale for mutation choice for screening be reevaluated? Prenat Diagn. 2008 Mar;28(3):236-41. doi: 10.1002/pd.1943. PMID: 18264947.
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Meetei AR, Sechi S, Wallisch M, et al. A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Mol Cell Biol. 2003;23:3417-26.
Mohaghegh P. Hickson ID. The Bloom syndrome helicase: keeping cancer at bay. Biologist (London). 2003;50:29-33.
Rassool FV, North PS, Mufti GJ, et al. Constitutive DNA damage is linked to DNA replication abnormalities in Bloom’s syndrome cells. Oncogene. 2003;22:8749-57.
Beamish H, Kedar P, Kaneko H, et al. Functional link between BLM defective in Bloom’s syndrome and the ataxia-telangiectasia-mutated protein, ATM. J Biol Chem. 2002;277:30515-23.
Honma M, Tadokoro S, Sakamoto H, et al. Chromosomal instability in B-lymphoblasotoid cell lines from Werner and Bloom syndrome patients. Mutat Res. 2002;520:15-
Langland G, Elliott J, Li Y, et al. The BLM helicase is necessary for normal DNA double-strand break repair. Cancer Res. 2002;62:2766-70.
Morimoto W, Kaneko H, Isogai K, et al. Expression of BLM (the causative gene for Bloom syndrome) and screening of Bloom syndrome. Int J Mol Med. 2002;10:95-99.
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INTERNET
Bajoghli A. Bloom Syndrome (Congenital Telangiectatic Erythema).Medscape. Updated: Updated: Apr 15, 2019. https://emedicine.medscape.com/article/1110271-overview. . Accessed Feb 13, 2024.
German J, Ellis NA. Bloom Syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G. eds. New York, NY: McGraw-Hill. https://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225074542 Accessed Feb 13, 2024.
Bloom Syndrome. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University.Entry No: 210900. Last Edited 07/17/2023. Available at: https://omim.org/entry/210900 Accessed Feb 13, 2024.
Langer K, Cunniff CM, Kucine N. Bloom Syndrome. 2006 Mar 22 [Updated 2023 Oct 12]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1398/ Accessed Feb 13, 2024.
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